Developmental neurogenetic diseases can only be studied, and potentially treated, once systems to deliver and express genes in neuronal cells are developed. We will utilize herpes simplex virus (HSV) as a vector for expressing genes in neuronal cells. This human DNA virus, for which about 90% of the U.S. population is seropositive, forms latent infections which persist for the lifetime of the individual. Using HSV derived vectors, we will study the nervous system component of a lysosomal storage disease. Lysosomal storage in neurons results in severe mental retardation in most children with these diseases. Specifically, we will use a bets- glucuronidase-negative-mouse (gusmps/gusmps), with mucopolysacharidosis (MPS) type VII (Sly disease), as an animal model. Experiments will be performed to insert a beta-glucuronidase gene into HSV- 1, under control of the viral promoter that is active during latency. This is the only HSV-1 promoter known to be active long-term in vivo. Animals will be infected with recombinant virus, or with a HSV-1 derived amplicon vector, and beta-glucuronidase gene expression will be studied. The ability of beta-glucuronidase enzyme expressed in latently infected animals to alter lysosomal storage during the life of these animals will be monitored histologically and biochemically. Both the HSV vector and the beta-glucuronidase gene will be engineered for maximal expression and spread of enzyme activity throughout the nervous system. The goal of these studies is to address the problem of treatment of neurogenetic diseases by developing a method of expressing genes in the nervous system in vivo using a ubiquitous human virus. These studies will also provide a method for studying gene regulation in neuronal cells in vivo using the state of the art techniques of molecular biology.